Phencyclidine (PCP), pharmacologically classified as a dissociative anesthetic, is best known as a widely abuse drug with potent psychotomimeti properties. Evidence that PCP binds with high affinity and spccifici(y to a unique class of membrane receptor in the mammalian CNS has given rise to speculation that the CNS contains a yet-to-be-identified PCP-like peptidergic neuromodulator and that dysfunction of this neuromodulatory system might underly psychotic disorders such as schizophrenia. It was recently shown that PCP receptors are physically co-localized with N-methyl-Daspartate (NMDA) receptors (a subtype of glutamate receptor) and that PCP powerfully antagonizes NMDA receptor-mediated excitatory and neurotoxic (excitotoxic) phenomena. MK-801 is a PCP-like compound which displays even greater potency than PCP in binding to the PCP receptor and in antagonizing the excitatory and toxic actions of NMDA. We and others hav shown that MK-801 and PCP can protect CNS neurons against hypoxic/ischemic or epilepsy-related brain damage (both of which are considered NMDA receptor-mediated processes). However, very recently we discovered that, quite separately from their neuroprotective properties, PCP and MK. 801 reproducibly induce pathomorphological changes in certain CNS neuronal populations when administered sub-cutaneously in subanesthetic doses. These findings raise new questions regarding the safety of these agents for use in the clinical management of neurodegenerative diseases, and suggest thec possibility that the neuronal populations selectively vulnerable to the neurotoxic actions of PCP might be the same populations through which the psychotoxic (psychotomimetic) actions of PCP are mediated, in which case further study of these neurons and the mechanisms underlying their peculiar vulnerability to PCP toxicity might eventually yield clues relevant to the pathophysiology of schizophrenia. Our findings also raise new questions concerning the nature and degree of risk associated with the use of PCP as a "recreational" drug. The aims of this proposal are to better characterize this newly discovered PCP neurotoxic syndrome and further investigate the underlying mechanism(s).